Am J Physiol Regul Integr Comp Physiol 285: R1-R13, 2003;
doi:10.1152/ajpregu.00535.2002
0363-6119/03 $5.00
INVITED REVIEW
The kallikrein-kinin and the renin-angiotensin systems have a multilayered interaction
Alvin H. Schmaier
Division of Hematology and Oncology, Department of Internal Medicine and Pathology, The University of Michigan, Ann Arbor, Michigan 48109-0640
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ABSTRACT
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Understanding the physiological role of the plasma kallikrein-kinin system (KKS) has been hampered by not knowing how the proteins of this proteolytic system, when assembled in the intravascular compartment, become activated under physiological conditions. Recent studies indicate that the enzyme
prolylcarboxypeptidase, an ANG II inactivating enzyme, is a prekallikrein
activator. The ability of prolylcarboxypeptidase to act in the KKS and the
renin-angiotensin system (RAS) indicates a novel interaction between these two
systems. This interaction, along with the roles of angiotensin converting
enzyme, cross talk between bradykinin and
angiotensin-(1–7)
action, and the opposite effects of activation of the ANG II receptors 1 and 2
support a hypothesis that the plasma KKS counterbalances the RAS. This review
examines the interaction and cross talk between these two protein systems.
This analysis suggests that there is a multilayered interaction between these
two systems that are important for a wide array of physiological
functions.
bradykinin; angiotensin; prolylcarboxypeptidase; angiotensin converting enzyme; angiotensin receptors; bradykinin receptors; ACE; ACE2; kininogen; prorenin
THE MECHANISM FOR ACTIVATION of the plasma kallikrein-kinin system (KKS) has been elusive. Although it is well known that the plasma KKS becomes activated when exposed to a negatively charged surface, hence its name the "contact system," a comprehensive physiological, negatively
charged surface has never been discovered. We observe that when the proteins
of the plasma KKS assemble on endothelial cells or their matrix on a
multiprotein receptor complex, the zymogen plasma prekallikrein (PK) becomes
activated to plasma kallikrein
(81,
90,
91). Our efforts to identify
an endothelial cell-associated plasma PK activator recognized that the enzyme
prolylcarboxypeptidase (lysosomal carboxypeptidase, angiotensinase C, PRCP,
PCP) has this property (88,
118). Inasmuch as PRCP had
only been previously proposed as a degrading enzyme of ANG II, the recognition
that it also functions as a PK activator indicates a new interaction between
KKS and the renin-angiotensin system (RAS)
(99,
116). This interaction, along
with the many other communications between these two systems, has led us to
formulate a new hypothesis for the physiological activity of the plasma KKS.
The plasma KKS serves as the physiological counterbalance to the RAS
(116). The purpose of this
review is to describe the intimacy and profundity of the interaction between
these two systems. These places of interaction serve as foci to examine this
hypothesis in the future in both in vitro and in vivo models.
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INTERACTIONS BETWEEN THE PLASMA KKS AND RAS
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Figure 1 presents a schema on the interactions between the KKS and the RAS. The assembly of high molecular weight kininogen (HK) and PK on endothelial cells results in PRCP activation of PK to plasma kallikrein
(118,
119). Plasma kallikrein has
several substrates in these systems. It autodigests HK or, at lower affinity,
low molecular weight kininogen (LK), to liberate bradykinin (BK). The
residual, cleaved HK (HKa) participates in its many activities such as
cysteine protease inhibition, anti-angiogenesis, and anti-proliferation of
cell growth (23,
63,
51). Alternatively, BK, HK,
LK, and tissue kallikrein are proangiogenic
(Table 1)
(24,
39). Not shown on
Fig. 1, plasma kallikrein also
converts factor XII to its activated forms and favorably activates
single-chain urokinase activation to two-chain urokinase
(90,
107). Plasma and tissue
kallikreins have also been recognized to be one of the activators of prorenin
to renin, an older observation whose physiological significance is questioned
(Fig. 1). Renin, an aspartyl
protease, activates angiotensinogen to ANG I. Angiotensin converting enzyme
(ACE) has the bifunctional activity of being one of the degrading peptidases
(kininase II) of BK and converting the inactive 10-amino acid ANG I to the
biologically active 8-amino acid peptide ANG II [ANG-(1–8)]. ACE is
another regulatory juncture point between these two systems
(Fig. 1). Liberated BK
stimulates vasodilation, nitric oxide (NO) formation, tissue plasminogen
activator (tPA) liberation, prostacyclin formation, and superoxide formation
(61,
62,
102,
126). BK also results in
lowering of blood pressure. BK and its ACE breakdown product BK-(1–5)
inhibit thrombin-induced platelet activation
(55). ANG II counterbalances
some of the activities of BK. Although ANG II can stimulate superoxide and NO
formation like BK (30), it
induces local vasoconstriction and contributes to elevation of blood pressure.
ANG II also directly stimulates tissue factor production and plasminogen
activator inhibitor 1 release
(97,
138). PRCP degrades ANG II to
form angiotensin-(1–7) along with ACE2 and, possibly, neutral
endopeptidase 24.11 (45,
139). Previously
angiotensin-(1–7) was believed to be an inactive breakdown product of
ANG II, but it too has been recognized to have biologic activities that result
in vasodilation and blood pressure lowering
(134). Last, stimulation of
the BK B2 receptor (BKB2R) and ANG II receptor result in
vasodilation and NO and prostacyclin formation, whereas stimulation of the ANG
I receptor results in vasoconstriction and blood pressure elevation
(Fig. 1). Thus there appears to
be many interaction points and a number of counterbalancing influences of each
of these systems on the other in health and inflammatory diseases
(10).
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Fig. 1. Interaction of the plasma kallikrein/kinin system (KKS) with the renin-angiotensin system (RAS). HK, high molecular weight kininogen; PK, prekallikrein; PRCP, prolylcarboxypeptidase; HKa, plasma kallikrein-cleaved, high molecular weight kininogen free of bradykinin; ACE, ANG I converting
enzyme; ACE2, angiotensin converting enzyme 2; tPA, tissue plasminogen
activator; PAI-1, plasminogen activator inhibitor 1; PGI2,
prostaglandin I2 or prostacylin.
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It is the intent of this review to examine each of these interactions in more detail and ascertain their relative importance as determined by in vitro and in vivo studies. In particular, the role of ACE in activating ANG I and inactivating BK will be discussed. The contribution of plasma kallikrein to
prorenin activation will be reexamined in light of a physiological mechanism
for PK activation. The summating biologic effects of BK and
angiotensin-(1–7) will be studied. The role of PRCP in ANG II
degradation and plasma PK activation will be presented. The modifying
influence of angiotensin receptors 1 and 2 on these systems also will be
reviewed. Finally the counterbalancing effect of each of these systems on
thrombosis, fibrinolysis, and angiogenesis will be introduced.
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ACE
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The first recognized important link between the plasma KKS and RAS was the discovery by Erdös and colleagues (46, 143,
146,
147) that kininase II, a
major BK degrading enzyme liberating the
Phe8,Arg9-dipeptide, was ACE. BK is the preferred
substrate of ACE over ANG I with a Km of 0.18 µM and a
kcat/Km ratio 
20 times higher
(45,
69). Recently, a homologue of
ACE, angiotensin converting enzyme 2 (ACE2), has been recognized
(8,
26,
35,
131). ACE2 has a different
substrate specificity than ACE (Fig.
2). ACE2 is a carboxypeptidase mainly located in the heart,
kidney, and testis. It degrades ANG I by removing the COOH-terminal lysine,
making the peptide angiotensin-(1–9), which has been reported to enhance
arachidonic acid release by BK and resensitize the BKB2R
(8,
84). Alternatively, ACE
degrades ANG I by proteolyzing it at the penultimate phenylalanine to produce
ANG II [angiotensin-(1–8)] (Fig.
2). ACE2 is 100-fold kinetically better degrading enzyme of ANG II
to angiotensin-(1–7) than prolylcarboxypeptidase (Km
of inactivation of 2 vs. 200 µM)
(99,
139). Thus, in those tissues
where ACE2 is present, it is the preferred angiotensinase. The two converting
enzymes also have different specificities to BK. ACE2 does not degrade BK, but
degrades des-Arg9-BK at its carboxy terminal amino acid
(35)
(Fig. 2). The implications of
these findings are not completely understood at this time. BK is the preferred
agonist for the constitutively present BKB2R and it usually lowers blood
pressure. Des-Arg9-BK is the preferred agonist for the BK
B1 receptor (BKB1R), which can become quickly expressed in
inflammatory states, resulting in elevation of blood pressure
(95). Thus different
converting enzymes may modulate the degradation of the different forms of BK
that have similar biologic activity under different stresses. The modulation
of the expression of BK and des-Arg9-BK by the two converting
enzymes may be another level of interaction between the KKS and the RAS.
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Fig. 2. Degradation pathways for ANG I and bradykinins (BKs) by the angiotensin converting enzymes. desArg9BK, des-Arg9-BK; ATII, ANG II; BK 1–7, BK-(1–7); BK 1–5, BK-(1–5); BKB2R, BK B2 receptor; BKB1R, BK B1 receptor; AT1R, ANG
II receptor 1; AT2R, ANG II receptor 2; Ang(1–7)R?,
hypothesized angiotensin-(1–7) receptor. It is important to appreciate
that ANG II can stimulate both the angiotensin 1 and 2 receptors. Likewise,
angiotensin-(1–7) can stimulate both angiotensin receptors and may have
its own receptor, Ang(1–7)R, that has yet to be physically
identified.
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The influence of ACE and possibly ACE2 on BK metabolism has more profound effects than just modulating blood pressure. The effects of ACE on BK metabolism have been recognized by the influence of ACE inhibitors (ACEI) on a number of biologic processes. ACEI have been shown in a large clinical trial
to result in a 25% reduction in death from cardiovascular disease, 20%
reduction in myocardial infarction, 30% reduction in stroke, 22% reduction in
heart failure, and 16% reduction in complications related to diabetes
(130). Although there is no
consensus of opinion as to the mechanism of protection from arterial
thrombosis, it may be due to an elevation of BK as result of reduced
metabolism. ACEI also may reduce the risk for thrombosis by decreasing ANG II
formation, thus lowering tissue factor and plasminogen activator inhibitor 1
production. BK elevation after ACEI treatment improves left ventricular
diastolic dysfunction by modifying NO release
(50). In the endothelial cell
NO synthase knockout mouse, there is a significant decrease in the
cardioprotective effects of ACEI
(76). The ability of ACEI to
improve insulin resistance in diabetic mice is mediated by BK and NO, because
HOE140, a BKB2R antagonist, and L-NAME, an NO synthase inhibitor,
block the enhancement of glucose uptake the agent
(120). Last, the mechanism by
which ACEI reduces the progression of various fibrotic renal diseases in
animal models may be mediated by BK
(115). In the
BKB2R-/- mouse or in mice treated with the
BKB2R antagonist HOE140, there is increased interstitial fibrosis and
decreased overall plasminogen activator and metalloproteinase-2 enzymatic
activity (115). This
information, although supporting the hypothesis that ACEI mediates much of its
actions through elevation of BK, has to be interpreted with caution, because
there may be strain differences in the mice used.
BKB2R-/- mice in a J129 background carry two
renin genes, one of which is not regulated by sodium. These animals develop
hypertension, cardiac hypertrophy, and reparative fibrosis that is reversed by
lifelong angiotensin 1 receptor blockade
(38,
79). This phenotype may be
less in BKB2R-/- mice backcrossed into a stable BL6 background that carries
one renin gene.
In addition to influencing BK degradation, ACEI influences BK activity. ACEI increases BK-related effects by an interaction with the BKB2R itself that increases the intrinsic activity of unoccupied BKB2R molecules (58,
59). Alternatively, it has
been proposed that ACEI interfere with the sequestration of the BKB2R in cell
membranes (7). More recent
evidence indicates that the increase in the concentration of ACE by ACEI
augments activation of the BKB2R by BK
(85). In addition to an effect
on the BKB2R, ACEI directly activate human BKB1Rs in the absence of ACE and
the BKB1R agonist, des-Arg10,Lys1-BK
(66). Enalaprilat or
ramiprilat, but not lisinopril, binds and activates the zinc binding motif,
H195EXXH199, on the BKB1R to stimulate calcium
mobilization (66). Last,
chronic ACEI administration is associated with functional vascular and renal
BKB1R, but not BKB2R, induction
(83). These latter data
suggest that ACEI also influence the inflammatory systems that regulate BKB1R
expression. The full implications of this upregulation of the BKB1R are not
completely known at this time.
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PRORENIN ACTIVATION
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Over 20 years ago, both plasma and tissue kallikreins had been proposed as activators of prorenin (Fig. 1). Sealey et al. (113) presented a hypothesis
that plasma kallikrein is an activator of plasma prorenin. The basis of this
hypothesis was that prorenin activation in plasma could occur after
cryoinactivation of plasma protease inhibitors and contact activation of
plasma both, promoting PK activation. Investigations by Derkx et al.
(33) indicated that after acid
activation of plasma, a technique that inactivates the plasma serpins, plasma
prorenin is activated and the level seen in PK-deficient plasma after
acidification is much less than that seen with normal plasma or trypsin.
Plasma kallikrein was shown to be the essential enzyme for prorenin activation
after factor XII activation of plasma
(114). The ability of plasma
kallikrein to activate prorenin after acid activation was confirmed by
inhibition of renin formation by Pro-Phe-Arg-CH2Cl
(89). To actually measure
renin formation in plasma activated by kaolin or cryoactivation, the plasma
serpins must be inactivated by acid treatment or removal by physical means
(9,
31). This mechanism for
prorenin activation fell into disfavor because neither cryoinactivation nor
contact activation have a physiological basis. Prorenin can be activated to
the aspartyl protease renin by acidification alone. Plasma kallikrein
activation of prorenin can occur at neutral pH, although acidification must be
used to eliminate the activity of the kallikrein neutralizing inhibitors
(32). Thus it is possible that
the kallikrein activation mechanism is an artifact. However, it was noted that
a total kininogen-deficient patient had reduced elevation of plasma renin when
assuming the upright position after salt loading
(142). These data support the
notion that plasma kallikrein may participate in prorenin expression. Because
prolylcarboxypeptidase, an endothelial cell membrane-associated PK activator,
has been identified, plasma prorenin may be activated under these
circumstances. This question should be examined again.
Tissue kallikreins have also been proposed as prorenin converting enzymes, although there is little information on how tissue prokallikrein is activated to tissue kallikrein. Porcine pancreatic kallikrein activates prorenin at an alkaline pH of 8.2 (64). Mouse
submandibular glandular tissue kallikrein activates mouse prorenin
(74). Mouse tissue kallikreins
mK1, mK9, mK13, and mK22 also have been shown to be prorenin activators
(73). Human hK1 activates
human prorenin (34). Although
plasma and tissue kallikrein along with cathepsin B and PC5 have been shown to
be activators of prorenin, it is still unsettled as to which of these enzymes
or any other is the major responsible prohormone convertase
(6,
94). Last, tissue kallikrein
knockout mice (KLK1-/-) have reduced renal
renin mRNA compared with wild-type mice, but the
BKB2R-/- mice have increased renin mRNA
(133). The meaning of these
data is presently unknown. Tissue kallikrein could promote gene expressions of
renin; plasma kallikrein may be an activator of prorenin.
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INTERACTION BETWEEN ANGIOTENSIN-(1–7) AND BK
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The recognition that angiotensin-(1–7) has biologic activity embellishes the knowledge of the interaction between the RAS with the KKS and itself (109, 134). Angiotensin-(1–7)
is produced by ACE2 (Km = 2 µM) or
prolylcarboxypeptidase (Km = 200 µM) degradation of ANG
II (99,
139)
(Fig. 3). Neprilysin
(endopeptidase 24.11) and thimet oligopeptidase (endopeptidase 24.15) also can
produce angiotensin-(1–7) from the breakdown of ANG I
(45,
47,
51)
(Fig. 3). All of these enzymes
are directly or indirectly involved in BK metabolism. There may be other
angiotensinases as well, because ACE2 is only found in the heart, kidney, and
testis, and angiotensin-(1–7) is found ubiquitously throughout the
vasculature. Once formed, angiotensin-(1–7) exerts its effects by
binding to the angiotensin receptor 1 in some cases to antagonize ANG II and,
in other cases, to the angiotensin receptor 2
(60,
110)
(Fig. 2). Angiotensin-(1–7) may also have its own receptor
(47,
67,
75)
(Fig. 2).
Angiotensin-(1–7) also is degraded by ACE
(Fig. 3). The interactions
between angiotensin-(1–7) and the KKS have been best studied in the
kidney (111). In essence,
there are two kinds of interactions between BK and angiotensin-(1–7):
potentiation of BK by angiotensin-(1–7) and mediation of the vascular
activity of angiotensin-(1–7) by BK
(111).
Angiotensin-(1–7) potentiates the hypotensive effect and vasodilation
action of BK in the normotensive or hypertensive rat and in rat mesenteric
vessels, respectively. Evidence that angiotensin-(1–7) action is
mediated by BK is provided by the observation that HOE140 blocks some
angiotensin-(1–7)-mediated activity
(111).
Angiotensin-(1–7) by stimulating the angiotensin 2 receptor may
stimulate BK release
(136)
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Fig. 3. Detailed ANG I degradation pathways. EP24.11, endopeptidase 24.11, neprilysin; EP24.15, endopeptidase 24.15; thimet oligopeptidase.
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Angiotensin-(1–7) has been described as the most pleotropic metabolite of ANG I, manifesting actions often the opposite of those described for ANG II (47). It dilates canine coronary arteries through kinins and NO
(11). Angiotensin-(1–7)
augments BK by locally acting as a synergistic modulator of kinin-induced
vasodilation by inhibiting ACE and releasing NO
(103). These investigations
in isolated aortic rings were confirmed by animal studies in rats.
Angiotensin-(1–7) decreases blood pressure in the rat, and this effect
is mediated by the BKB2R and is unaffected by angiotensin receptor 1 and 2
antagonists (1).
Angiotensin-(1–7) is both a substrate and inhibitor of ACE
(29). It potentiates
arachidonic acid release by an ACE-resistant BK analog acting on BKB2Rs
(29). Vasodilation and NO
formation induced by angiotensin-(1–7) result from indirect potentiation
of BK as an agonist of the BKB2R
(29). Angiotensin-(1–7)
along with angiotensin-(1–9) also may potentiate the effects of BK by
inducing cross talk between ACE and the BKB2R
(84). Because ACE inhibitors
block desensitization of the BKB2R, angiotensin-(1–7) functions as an
ACE inhibitor blocking the ACE COOH domain
(29,
132). In doing so,
angiotensin-(1–7) acts synergistically with NH2
domain-specific ACE inhibitors
(29,
132). Both
angiotensin-(1–9) and angiotensin-(1–7) potentiate BK's action on
the BKB2R to elevate arachidonic acid and NO release to occur at lower
concentrations (0.01–0.1 µM) than the IC50 (1.2 µM) for
ACE inhibition (29,
68). This finding indicates
that angiotensin-(1–7) potentates BK by another mechanism independent of
ACE inhibition. ACE inhibition results in reduced ANG II vasoconstriction and
increased angiotensin-(1–7) in plasma and tissue, resulting in
vasodilation (108). In human
internal mammary arteries, contractions induced by ANG I and II and a
non-ACE-specific substrate, Pro11,D-Ala12-ANG
I, are antagonized by angiotensin-(1–7)
(108). Topical application of
BK or angiotensin-(1–7) induces vasodilation in exposed rat mesenteric
vessels, and this phenomenon is abolished by the BKB2R antagonist HOE140 or
the angiotensin-(1–7) antagonist A-779
(100). This result suggests
that each of these biologically active peptides is mediating this activity
through its own receptor system. This assessment is especially important for
angiotensin-(1–7), because its own receptor has yet to be identified.
The potentiation of BK-induced vasodilation by angiotensin-(1–7) is a
receptor-mediated phenomenon that is dependent on cyclooxygenase-related
products and NO release
(100).
Angiotensin-(1–7) significantly increases formation of cGMP and
NG-nitro-L-arginine methyl ester
(L-NAME), the NO synthase inhibitor, and a selective soluble
guanylate cyclase inhibitor blocks the angiotensin-(1–7)-induced
relaxations in canine middle cerebral arteries
(48). Finally,
angiotensin-(1–7) causes afferent rabbit arteriole dilatation and this
effect is mediated by NO and not cyclooxygenase products, suggesting a role
for kinins (106). Thus
angiotensin-(1–7) influences BK by inhibiting ACE, stimulating the
BKB2R, and possibly stimulating its own receptor that may cross talk with the
BK receptors (see below).
However, there are some data in animals and humans suggesting that the KKS does not counterbalance the RAS. Widdop et al. (141) found that angiotensin-(1–7) failed to enhance the hypotensive effects of BK in the
spontaneously hypertensive (SHR) and Wister-Kyoto rats. Furthermore,
angiotensin-(1–7) infusion for 7 days has a variable effect of blood
pressure in SHR (141).
Angiotensin-(1–7) infusion in the forearm of patients with heart failure
treated with an ACE inhibitor did not lower blood pressure nor potentiate the
vasodilating effects of BK
(28). This latter study should
not be considered definitive because the model is in a limited population of
patients heavily pretreated with medication. However, these animal and human
studies question the importance of angiotensin-(1–7) as a clinically
significant vasodilator. More animal and human models are needed to clarify
the physiological role of angiotensin-(1–7).
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PRCP
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The enzyme PRCP (lysosomal Pro-X carboxypeptidase, Pro-X carboxypeptidase, peptidyl prolylamino acid hydrolase, angiotensinase C) has been recognized as an ANG II degrading enzyme (99,
144). PRCP is a
carboxypeptidase discovered by Erdös and Yang
(144) when it was noted that
a pig kidney extract unexpectedly cleaved des-Arg9-BK at the
Pro7,Phe8-OH bond. The enzyme has an optimal pH for
activity 5, but, at pH 7, it retains 20–50% of its maximal activity
with physiological substrates. PRCP is a serine protease inhibitable by
diisopropyl fluorophosphate and PMSF
(118). It is also inhibited
by antipain, leupeptin, corn trypsin inhibitor, and high concentrations of
mercuric chloride. EDTA, o-phenanthrolone, iodoacetic acid,
iodoacetamide or benzamidine does not inhibit this enzyme
(118). Its physiological
inhibitor is not known. PRCP is purified from lysosomal fractions from kidney
homogenates and human umbilical vein endothelial cells
(98,
99,
118,
144,
145). Inasmuch as
angiotensin-(1–7) is found circulating in plasma and ACE2's location is
limited to certain organs, there must be a pool of PRCP expressed on the
external membrane of unperturbed endothelial cells
(109). This notion was
recently confirmed by the identification of PRCP on the external membrane of
cultured human umbilical vein endothelial cells and cell matrix by various
techniques (88,
118). Furthermore, recent
preliminary evidence indicates that the constitutive presence of PRCP activity
and antigen on cultured endothelial cells is blocked by treatment of the cells
with an antisense oligonucleotide
(119).
In addition to being a degrading enzyme of ANG II, PRCP has recently been recognized as a plasma PK activator that is independent of factor XIIa (118). The Km of PK activation by PRCP is 7–17 nM. These data
suggest that PRCP is a better PK activator than an ANG II degrading enzyme.
PRCP is the first endothelial cell PK activator that has been specifically
identified (90,
118). Recently, heat shock
protein 90 has been proposed as an endothelial cell activator of PK
(70,
71). Because this protein,
which is not an enzyme, was affinity purified on a corn trypsin inhibitor
affinity column, it may have contained trace quantities of PRCP sufficient to
activate PK (70,
71). PRCP activity is
neutralized by serine protease inhibitors and antibodies to this protein. It
is also present on endothelial cell matrix, another site where PK assembles to
become activated (88,
91). We can postulate that the
expression of PRCP results in ANG II degradation with the elimination of its
sodium retention ability and vasconstrictive activity to make
angiotensin-(1–7), a vasodilator. Furthermore, the ability of PRCP to
activate PK should result in BK liberation
(Fig. 1). Thus we can speculate
that the sum of PRCP activity is angiotensin-(1–7) formation and BK
release, resulting in increased NO formation, vasodilatation, and lowering of
blood pressure. These hypotheses need to be examined in the PRCP knockout
mouse.
Recent investigations with the C1 inhibitor (C1 INH) knockout mouse suggest that plasma kallikrein is constitutively present in the intravascular compartment to generate BK (54). The C1 INH KO mouse has
persistent paw edema that is blocked by C1 INH infusion, HOE140 infusion, or
mating of the C1 INH KO mouse with the
BKB2R-/- mouse
(54). Because C1 INH is one of
the major plasma protease inhibitors of plasma kallikrein, not tissue
kallikrein, formed plasma kallikrein must be constitutively present to
proteolyze kininogens and liberate BK to mediate the formation of the
angioedema. This animal model is consistent with studies in tissue culture
indicating that the assembly of HK and PK on endothelial cells results in
immediate PK activation by PRCP
(88,
90,
118,
119). These data also suggest
that in the intravascular compartment, constitutive activation of plasma PK
contributes to BK formation. Although no PK knockout mouse has been available
to know for certain, the present data suggest that plasma kallikrein
activation is an intravascular kininogenase for the constitutive expression of
BK.
This information on plasma PK has to be contrasted with good evidence for tissue kallikrein (KLK1) formation in the intravascular compartment. First, the physiological activator(s) of tissue PK is not known. Second, in cultured endothelial cells, tissue kallikrein mRNA, synthesis, antigen, and activity
are noted (30). Furthermore,
ANG II stimulation results in increased kallidin and BK production, suggesting
that there was increased KLK1 expression. ANG II elevation may result in
augmentation of vascular kinins through increased expression of tissue
kallikrein. Last, ANG II stimulated vasodilation of venous rings from
umbilical cords and this activity is attenuated by the KLK1 inhibitor CH694
(30). Recent studies in tissue
kallikrein (KLK1) knockout mice also indicate that these animals are unable to
generate significant levels of kinins in most tissues and develop
cardiovascular abnormalities early in adulthood despite normal blood pressure
(87). These animals also have
low kinin-generating activity in isolated tissues that is important for local
organ development (87). Tissue
kallikrein itself appears to be important for organ development and
angiogenesis (see below). Thus the Meneton et al.
(87) report indicates the
importance of tissue kallikrein in BK formation in tissues and the development
of the cardiovascular system. When the plasma PK knockout is created, the
relative importance of the two BK-generating enzymes on modulation of
intravascular BK and cardiovascular activity will need to be examined.
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ANGIOTENSIN RECEPTORS 1 AND 2
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The receptors for ANG II have been implicated in the cross talk between the RAS and KKS. The many layers of interaction between the KKS and RAS are shown in the communication of ANG II with its receptors. One could argue that the fine tuning between these systems contributes to the homeostasis of blood
pressure control and other biologic processes. Evidence for the interaction
between the RAS and KKS at the level of the angiotensin receptor was first
recognized by the finding that the RAS stimulates renal BK production and cGMP
formation through the ANG II receptor 2 (AT2)
(125). Inhibition of renin,
not the angiotensin 1 receptor, decreases renal BK levels during salt
depletion (125). This
investigation introduces the notion that stimulation of AT2
receptor releases BK and NO. In 1997, Liu and coworkers
(76) recognized that in
experimental heart failure, ACE inhibitors and ANG II receptor 1
(AT1) blockade have cardioprotective effects that are due to direct
effects on the heart or secondary hemodynamics mediated by BK derived from
activation of the AT2 receptor. The ability of ANG II to directly
stimulate renal BK production was confirmed in conscious rats, and this effect
is blocked by an AT2 receptor antagonist, but not by an
AT1 receptor antagonist, losartan
(123). Vasodilation produced
by stimulation of AT2 in stroke-prone hypertensive rats is produced
by BK and NO increasing aortic cGMP
(52). Similar findings were
made in AT2 receptor transgenic mice that overexpress the
AT2 receptor in vascular smooth muscle
(136). Furthermore, infusion
of ANG II into AT2 receptor transgenic mice abolishes the
AT1 receptor pressor effect, which is blocked by the BKB2R
antagonist HOE140 and NO synthase inhibitor L-NAME
(136). Moreover, removal of
endothelium eliminated these AT2 receptor-mediated effects. Thus
AT2 receptor-dependent vasodilation under flow conditions is
mediated by activation of the vascular kallikrein/kinin system with the
elaboration of BK (72). How
the AT2 receptor system leads to increased BK formation is not
known. It may be mediated by increased tissue kallikrein expression
(30). Alternatively, it is not
known whether ANG II influences PRCP, PK, or HK expression.
Although ANG II can stimulate the AT2 receptor to release NO, and indirectly BK, there is additional evidence that there also is an interaction between AT1 receptor and the BKB2R on a more fundamental level. The AT1 and BKB2Rs form stable heterodimers
causing increased activation of G
q- and
GI-proteins
(3,
4). Heterodimerization also
results in a change in the endocytic pathways of both receptors.
Heterodimerization between the AT1 and BKB2R occurs in platelets
and omental vessels in preeclamptic women
(3). This interaction results
in a four- to fivefold increase in protein levels of the BKB2R
(3). Last, the AT2
receptor binds AT1 receptors to form additional heterodimers to
antagonize AT1 receptor function
(2). These studies indicate
regulatory interactions between the two systems at the level of their receptor
proteins.
The clinical importance of the interactions between AT receptor system and the KKS has been examined in a number of studies. Young BKB2R null mice 10–12 wk old in a 129/SvEv background do not have a cardiac phenotype under normal physiological conditions
(148). When these animals are
aged over 12 mo, they develop hypertension and an increase in left ventricular
growth marked by chamber dilatation, elevation of left ventricular
end-diastolic pressure, and reparative fibrosis
(38,
80). This latter mouse
phenotype is prevented by treatment with ACE inhibitors or AT1
receptor antagonists (79,
148). In isolated rat hearts,
inhibition of the BKB2R with HOE140 increases myocardial ischemia/reperfusion
injury, and inhibition of the AT1 receptor with losartan reduces it
(112). AT1
receptor knockout mice have an activated KKS that amelio-rates the severity of
renal vascular disease (135).
In the developing kidney, there is much cross talk between the RAS and KKS.
High salt loads during gestation suppress the fetal RAS and provoke abnormal
renal development in the BKB2 knockout mouse backcrossed into stable C57BL/6J
background (36). Furthermore,
BK stimulates renin gene expression, renal kallikrein is regulated by a
negative feedback loop mediated by the BKB2R, and angiotensinogen, ACE, and
AT1 are not BK-targeted genes
(150). In rats,
AT2 receptor stimulation induces a systemic vasodilator response
mediated by BK and NO that counterbalances the vasoconstrictor action of ANG
II at the AT1 receptor
(19). This latter information
suggests that AT1 receptor blockage potentiates the cardiovascular
effects of ACE inhibitors in the heart and kidney
(124). ANG II infusion in the
BKB2R knockout animals in a stable C57BL/6J background vs. control induces
hypertension, suggesting that the KKS selectively buffers the vasoconstrictor
activity of ANG II (21).
Alternatively, ANG II infusion in rats in the presence of an AT1
antagonist elicited vascular relaxation that was blocked by a BKB2R antagonist
and was reduced in kininogen-deficient rats
(72). These animal data
suggest that in the presence of increased ANG II with stimulation of the
AT2 receptor, BK production is secondarily produced
(72,
137). The mechanisms that
modulate ANG II action on AT1 vs. AT2 receptors are not
completely known.
|
INTERACTIONS BETWEEN THE KKS AND RAS WITH THROMBOSIS, FIBRINOLYSIS, AND ANGIOGENESIS
|
|---|
Although the RAS and KKS are recognized as important modulators of vascular biology, blood pressure regulation, and vascular inflammation (10), they have also been examined for their influence on thrombosis, fibrinolysis, and angiogenesis.
Therapeutic manipulations of the RAS and KKS appear to result in risk
alteration for arterial thrombosis. Treatment with ACE inhibitors or
AT1 receptor antagonists results in an 15–20% decrease
in risk for myocardial infarction and stroke
(27,
130). Furthermore, ACE
inhibitor treatment before thrombolytic therapy reduces an early increase in
plasma plasminogen activator inhibitor 1 (PAI-1) levels in acute myocardial
infarction (140). The
experimental basis for these clinical results will be reviewed.
|
THE RAS IS PROTHROMBOTIC
|
|---|
The RAS has been proposed as a prothrombotic system (18). ANG II was recognized to increase plasminogen activator inhibitor-1 (PAI-1) mRNA, antigen, and activity levels from cultured astrocytes and endothelial cells in culture
(97,
101,
138). ANG II also increases
tissue factor mRNA and activity without affecting tPA or tissue factor
protease inhibitor in rat aortic endothelial cells
(97). Atrial natriuretic
peptide suppresses ANG II-induced expression of tissue factor and PAI-1 mRNA
in cultured rat aortic endothelial cells
(149). The vasodilating
peptide adrenomedullin blocks ANG II upregulation of tissue factor and PAI-1
mRNA in cultured rat endothelial cells
(128). In cultured vascular
smooth muscle cells, activation of MEK/ERK and Rho-kinase pathways contribute
to angiotensin-induced elevation of PAI-1 mRNA
(129). In cultured human
monocytes, ANG II increases tissue factor mRNA and antigen, but not PAI-1
(92). An ACE inhibitor
(captopril) and ANG II receptor 1 antagonist (candesartan) decrease tissue
factor levels in these cells. The levels of PAI-1 protein are also reduced by
captopril, but this effect is blocked by a BKB2R antagonist
(92).
Some support for the above findings in cultured cells has been seen by in vivo studies. Angiotensin infusion in Sprague-Dawley rats induces PAI-1 mRNA in all tissues, and that effect is blocked by an ANG II receptor 1 antagonist (93). However, it is not known
if this rise in PAI-1 levels increases the risk for thrombosis. Salt depletion
in normal individuals on an ACE inhibitor significantly decreases the 24-h
PAI-1 inhibitor activity and antigen levels
(13). An ACE inhibitor may
reduce the incidence of thrombotic events by reducing peak morning PAI-1
inhibitor levels. However, when the effects of an ACE inhibitor were compared
with an AT1 receptor antagonist in 25 normotensive individuals, ACE
inhibitor treatment, but not the AT1 receptor antagonist treatment,
lowered PAI-1 inhibitor activity and antigen levels
(12). In contrast, the
AT1 receptor antagonist reduces plasma tPA antigen levels, but the
ACE inhibitor does not (12).
Alternatively, when studied in 20 insulin-resistant hypertensive individuals,
an ACE inhibitor or an AT1 receptor antagonist significantly
reduced plasma PAI-1 antigen; however, the ACE inhibitor had a longer duration
of effect (16). These studies
are conflicting and indicate that these drugs may have different effects
depending on the well-being of the subject. Also, ANG II may elevate PAI-1
levels by mechanisms independent of the AT1 receptor and it may
downregulate expression of tPA. These studies also point to the complex
mechanism by which ACE inhibitors and AT1 receptor antagonists
protect from thrombosis in large clinical trials. Investigations in rats
suggest that the antithrombotic effects of ACE inhibitors and AT1
receptor antagonists may be mediated by angiotensin-(1–7)
(75). Angiotensin-(1–7)
infusion reduced thrombus weight and this effect was blocked by an
angiotensin-(1–7) antagonist (A-779), an AT1 receptor
antagonist (EXP 3174), but not by an AT2 receptor antagonist.
Furthermore, the antithrombotic effects of captopril or losartan were
attenuated by A-779 or L-NAME and indomethacin, a prostacyclin
inhibitor (75). However,
caution must be exercised overall on broadcasting the antithrombotic effects
of ACE1 or AT1 receptor antagonists. Recent studies indicate that a
thiazide-type diuretic was superior to ACEI or AT1 receptor
antagonism in preventing cardiovascular complications, indicating that the
antithrombotic effects of antihypertensives may be by another mechanism than
inhibition of the RAS (5).
Animal studies are needed to determine if stimulation of the RAS induces
thrombosis.
|
THE KKS IS PROFIBRINOLYTIC AND ANTITHROMBOTIC
|
|---|
As an alternative to the RAS, the KKS has been recognized to influence fibrinolysis since its original characterization. Factor XII deficiency was characterized over 40 years ago to have defective fibrinolysis (96). To date there have not
been good animal models to convincingly show that the plasma KKS is involved
in thrombosis. Plasma kallikrein, factor XIIa, and factor XIa have the ability
to activate plasminogen to plasmin, albeit much less efficiently than
tissue-type plasminogen activator and two-chain urokinase plasminogen
activator (22,
53,
82). However, plasma
kallikrein has been shown to be a kinetically favorable activator of
single-chain urokinase (65).
Activation of plasma PK when bound to HK on endothelial cells results in
kinetically favorable single-chain urokinase formation with subsequent plasmin
formation, suggesting that this pathway is the preferred route for plasmin
formation in vivo (90).
In addition to stimulating fibrinolysis by participating in single-chain urokinase activation, kallikrein-induced BK liberation influences fibrinolysis by stimulating tPA release from venous endothelium (15,
17,
126). The mechanism by which
BK liberates tPA from human vasculature is mediated through the BKB2R and is
independent of NO and prostacyclin liberation also induced by BK
(14). BK stimulation of
cyclooxygenase 2 (COX2) with the vasodilator prostacyclin liberation also
contributes to the anticoagulant state
(49,
62,
105). Stimulation of COX2 in
mice also results in increased renal medullary blood flow, increased urine
flow, and reduced pressor effects of ANG II, contributing to the
antithrombotic state
(105).
In addition to the profibrinolytic activity of the plasma KKS, there is evidence to suggest that this system is antithrombotic. HK and LK were found to inhibit thrombin-induced platelet aggregation (86,
104). In total
kininogen-deficient plasma, there is a lower threshold for gamma
thrombin-induced platelet activation than in normal plasma
(104). The HK-deficient rat
also has a lower threshold for thrombosis than a normal rat
(25). The thrombin inhibitory
region on kininogens was found to be minimally contained in the ACE breakdown
product of BK, BK-(1–5), Arg-Pro-Pro-Gly-Phe (RPPGF)
(55). High concentrations of
RPPGF prevent coronary thrombosis in the dog using the Lucchesi model of
electrolytic injury and in the Folt's model of cyclic flow variations
(56,
57). It is presently unclear
whether there is a sufficient physiological elevation of the ACE breakdown
product of BK (RPPGF) to contribute to the constitutive anticoagulant nature
of the intravascular compartment. However, recent preliminary results suggest
that it may be possible. The BKB2R-/- mouse
in a J129/B6 background has delayed time to arterial thrombosis using the Rose
Bengal model of carotid artery thrombosis
(127). Infusion of RPPGF or
HOE140 into control J129/B6 mice delays the time to arterial thrombosis in
these mice. These animal data conflict with in vitro studies and in vivo data
indicating that BK administration is a potent liberator of tPA release
(15,
17,
126). Further investigations
are necessary to understand the physiological sum of the anticoagulant,
antithrombotic mechanism(s) of the plasma KKS.
|
THE INTERACTION OF THE PLASMA KKS AND RAS IN ANGIOGENESIS
|
|---|
The influence of the KKS and RAS on angiogenesis has recently been appreciated (Table 1). It has been known for some time that BK may have some proangiogenic effects. BK stimulates a neovascular response in implanted sponges in the rat and new
vessel formation is blocked by [Leu8]des-Arg9-BK
(63). More recently, intact HK
and LK also have been shown to be proangiogenic
(24). A monoclonal antibody
directed to HK's domain 5 blocks HK-induced angiogenesis probably by
interfering with kallikrein cleavage of the HK to liberate BK
(24,
117). Alternatively, plasma
kallikrein-cleaved HK (HKa) (kininostatin), recombinant domain 5 of HK, and
isolated peptides from the domain 5 region inhibit angiogenesis and cell
proliferation and growth (23,
151).
Upregulating the KKS or interfering with the RAS influences angiogenesis. The interaction between BK and ANG II appears to be essential for normal cardiac development. BKB2R-/- mice treated from birth with an AT1 receptor antagonist have reduced left
ventricular mass, chamber volume, wall thickness, and myocardial fibrosis than
animals left untreated (37,
78). These data suggest that
ANG II is intimately involved in the cardiac development.
The components of the RAS are intimately involved in reparative angiogenesis. In limb ischemia models, the AT1 receptor is involved in and necessary for reparative angiogenesis (43). AT1 receptor
blockade or ACE inhibition delays postischemic reparative processes
(43). However, proangiogenic
activity is not unique to ANG II. ACE inhibitors, HOE140, or the absence of
the BKB2R results in reduced intimal hyperplasia produced by interrupted
carotid blood flow in mice
(41). These data, along with
evidence that ACE inhibitors increased vessel density and capillary number in
a model of surgically induced hindlimb ischemia in wild-type but not
BKB2R-/- mice indicate that the BKB2R
mediates the proangiogenic effect of these drugs
(121). Furthermore, a
low-dose combination of an ACE inhibitor and the diuretic indapamide induces
neovascularization in ischemic rat hindlimbs
(122). Gene transfer of
tissue kallikrein increased urinary kinins, cGMP, and cAMP and had a
protective effect on neointima formation
(40). This protective effect
was not seen when gene transfer was performed in the
BKB2R-/- mouse
(40). In other investigations,
the SHR was also found to have impaired reparative angiogenesis
(42). Gene transfer of the
human tissue kallikrein gene augmented capillary density and restored the
physiological angiogenic response needed for wound healing in this animal
(39).
In addition to ANG II and the BKB2R, other components of the KKS and RAS contribute to angiogenesis. The BKB1R also participates in angiogenic reparative processes. In cells in culture, stimulation of the BKB1R initiates endothelial cell proliferation and survival; antagonism of this receptor
results in apoptosis (44). In
a murine model of limb ischemia, interference with BKB1R signaling inhibits
the native angiogenic response to ischemia. The BKB1R knockout animals are
susceptible to limb necrosis after limb ischemia
(44). Alternatively, local
delivery of a BKB1R agonist enhances collateral vascular growth and
accelerated perfusion recovery
(44). Last, angiotensinogen
and its cleaved derivatives interfere with angiogenesis
(20). Because angiotensinogen
is a serpin and antithrombin has a strong antiangiogenic activity,
investigations showed that angiotensinogen and its derivatives [reactive loop
cleaved form, and des(ANG I)angiotensinogen] have antiangiogenic activity
(20). In sum, these data
suggest that breakdown products of protein components of the KKS and RAS are
antiangiogenic, whereas intact proteins and defined physiological biologically
active peptides are proangiogenic (Table
1).
|
SUMMARY
|
|---|
This review indicates that the plasma KKS and RAS are thoroughly intertwined throughout the cardiovascular system. Activation of one system probably results in a counteractivation of some aspect of the other proteolytic system to maintain physiological homeostasis. In the information
reviewed, the interaction of both pathways at the whole protein level and the
successive enzymatic breakdown products of their biologically active peptides
is multilayered and profound. Presently, a few critical juncture points in
these systems have been recognized as drug targets. More drug targets for the
treatment of cardiovascular disease related to these two systems can be
developed by better understanding of the interactions of these systems.
|
ACKNOWLEDGMENTS
|
|---|
I thank Drs. A. Hasan, Z. Shariat-Madar, G. da Motta and Ms. F. Mahdi for contributions to the evolution of these ideas.
|
FOOTNOTES
|
|---|
Address for reprint requests and other correspondence: A. H. Schmaier, The Univ. of Michigan, 5301 MSRB III, 1150 West Medical Center Dr., Ann Arbor, MI 48109-0640 (E-mail:
aschmaie{at}umich.edu).
|
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ABSTRACT
INTERACTIONS BETWEEN THE PLASMA...
